Dosage forms comprising polymers comprising different molecular weights

ABSTRACT

A dosage form is disclosed comprising a wall surrounding a compartment, which comprises a first composition comprising a carboxymethylcellulose and a second composition comprising a higher molecular weigh carboxymethylcellulose. The first composition comprises a dosage amount of drug that delivers from the dosage form at a controlled rate over time.

FIELD OF THE INVENTION

The present invention pertains to a dosage form with improved drugdelivery capabilities. More particularly, the dosage form comprises afirst composition comprising a drug and a carboxymethylcellulose, and asecond composition comprising a carboxymethylcellulose comprising ahigher molecular weight then the carboxymethylcellulose in the firstcomposition. The first and second compositions cooperate to deliver amaximum dose of drug with a minimum of residual drug left in the dosageform.

BACKGROUND OF THE INVENTION

Controlled release dosage forms are increasingly important fordelivering drugs to an animal for obtaining good therapy. The controlledrelease of drug by a dosage form indicates control is exercised overboth the duration and the profile of a drug release program. Controlledrelease dosage forms provide many therapeutic advantages overconventional dosage forms. For example, one major and importantadvantage is the lessening of fluctuation in blood plasma drugconcentrations. The pharmacologic basis for minimizing fluctuations inplasma level derives from three therapeutic principles. First, everydrug has a therapeutic blood level that must be reached if the desiredtherapeutic benefit is to be achieved from the administered drug.Second, most drugs have blood plasma levels that define the limits abovewhich side effects may appear, and this can be substantially avoided bythe used of controlled release dosage forms. Third, the drug plasmaconcentration response for most drugs is proportional to theconcentration administered, which dictates of the need for controlledrelease dosage forms. These pharmacologic principles indicate a need forkeeping plasma concentrations within a therapeutic level, andaccordingly, addresses the need for a controlled release dosage form toachieve the intended results.

The dosage form used for drug administration can influence the course oftherapeutic activity by affecting the profile of drug concentration inthe blood. For example, the blood level profile of a drug followingadministration by a prior art conventional dosage form is defined by aninitial high peak, followed by a rapid decline, in both the slope andthe duration of the drug The initial high peak typically substantiallyexceeds the therapeutic plasma concentration range and the levelfluctuates in peaks and troughs above and below the desired therapeuticlevel. In contrast, controlled release dosage forms can minimize thefluctuations known to the prior art, minimize or even avoid the peaks inblood level concentration and the following valley in blood levelconcentrations A controlled dosage form can extend also the duration oftherapeutic index levels over time.

In view of the above presentation it is immediately evident a pressingneed exists for a controlled release dosage form for administering atherapeutically-important drug, such as a calcium channel blocking drugto a patient in need of calcium channel blocking therapy The expression"calcium channel blocking drugs" also are known as calcium channelblockers, calcium channel antagonist, or calcium antagonists. Thecalcium channel blockers possess broad pharmacological use and theyexhibit pronounced properties such as long-lasting vasodilating effectsaccompanied by an energy-sparing effect on cardiac metabolism,antiarrhythmic and antianginal action on cardiac muscle, vascularspasmolytic action, antihypertensive action, spasmolytic action onsmooth muscle of the gastrointestinal and urogenital tracts and thecerebrovascular and respiratory system, useful forantihypercholesterolemic action, protection of the ischemic myocardium,inhibition of irritable bowel syndrome and esophagal spasm, inhibitionof migraine, inhibit vascular calcium contraction, reduce cardiaccontractile force, inhibit calcium mediated tracheal contraction,inhibit calcium uptake in primary cells, myocardial ischemia andhypertension. The calcium antagonist drugs that possess thesetherapeutic properties and can be administered by the dosage form andthe method of the invention comprise a member selected from the groupconsisting of verapamil, nifedipine, diltiazem, bepridil, nicardipine,nitredipine, isradipine, niludepine, nisoldipine, felodipine,cinnarizine, flunarizine, perhexiline, amlodipine, or as theirpharmaceutically acceptable salts or as their pharmaceuticallyacceptable derivatives. The pharmaceutically acceptable salts are acidaddition salts of non-toxic pharmaceutically acceptable acids. The acidsinclude inorganic acids and organic acids, and consequently, the saltcan be an inorganic or organic salt. The pharmaceutically acceptablesalts for the purpose of this invention consist of a member selectedfrom the group consisting of inorganic, hydrochloric, hydrobromic,hydriodic, phosphoric, sulfuric, nitric, and the like, organic,trifluoroacetic, trichloroacetic, acetic, glycolic, pamoic, pyruvic,malonic, succinic, maleic, fumaric, malic, tartaric, citric, mandelic,benzoic, cinnamic, methane sulfonic, ethane sulfonic, salicylic,p-toluenesulfonic or cyclohexanesulfamic. The pharmaceuticallyacceptable derivatives include alkyl substituted and ester derivatives.The drugs are known to the medical art in USAN and the USP Dictionary ofDrug Names, 1961-1990 Cumulative List, published 1990 by United StatesPharmacopeial Convention, Inc.; and in Physician's Desk Reference, 45Ed. 1991, published by Medical Economy Company, Inc.

BACKGROUND PRIOR ART

Dosage forms manufactured as osmotic devices for delivering a drug to anenvironment of use are known to the prior art in U.S. Pat. No. 3,845,770issued to Felix Theeuwes and Takeru Higuchi and in U.S. Pat. No.3,916,899, issued to the same patentees. The osmotic devices disclosedin those patents comprise a semipermeable wall that surrounds acompartment containing a drug. The wall is permeable to the passage ofan external fluid, and substantially impermeable to the passage of drug.There is a passageway through the wall for delivering the drug from thedevice. These devices release drug by fluid being imbibed through thewall into the compartment at a rate determined by the permeability ofthe wall and the osmotic pressure gradient across the wall to produce anaqueous solution containing drug that is dispensed through thepassageway from the device. These devices are effective for delivering adrug in an aqueous solution but often they do not contemplate deliveringsubstantially all of the drug present in a thixotropic pharmaceuticallyacceptable carrier.

A pioneer advancement in osmotic delivery devices was presented to theart by inventor Felix Theeuwes in U.S. Pat. No. 4,111,202. In thispatent, the delivery kinetics of the device are enhanced, for deliveringdrugs with degrees of solubility in aqueous fluids that are difficult todeliver, such as very soluble or insoluble in the fluid, bymanufacturing the device with a drug compartment and an osmagentcompartment separated by a film, which film is movable from a rested oressentially straight position to a curved position. The device deliversdrugs by fluid being imbibed through the wall into the osmagentcompartment producing a solution that causes the compartment to increasein volume and act as a driving force that is applied against the film.This force urges the film to expand against the drug compartment andcorrespondingly diminish the volume of this compartment, whereby drug isdispensed through the passageway from the device. While this deviceoperates successfully for its intended use, and while it can delivernumerous difficult to deliver drugs, its use can be limited because ofthe manufacturing steps needed for fabricating and placing the movablefilm in the device.

In U.S. Pat. No. 4,327,725 patentees Cortese and Theeuwes provided anosmotic dispensing device for delivering beneficial drugs that, becauseof their solubilities in aqueous and biological fluids, are difficult todeliver in meaningful amounts at controlled rates over time. The osmoticdevices of this patent U.S. Pat. No. 4,327,725 comprise a semipermeablewall surrounding a compartment containing a beneficial drug that isinsoluble to very soluble in aqueous and biological fluids. The devicealso contains an expandable hydrogel. In operation, the hydrogel expandsin the presence of external fluid that is imbibed into the device andpushes an aqueous drug solution through the passageway from the device.This device operates successfully for its intended use, and it deliversmany difficult to deliver beneficial drugs for their intended purpose.However, it has been observed, its use often can be limited because thehydrogel can lack a present ability to imbibe sufficient fluid for themaximum self-expansion needed for pushing all beneficial drugs from thedevice.

In U.S. Pat. No. 4,765,989 and in U.S. Pat. No. 4,783,337, both patentsissued to patentees Wong, Barclay, Deters and Theeuwes, there isprovided a novel delivery device for delivering a drug to a patient inneed of therapy. The delivery device in these patents comprise a wallpermeable to fluid and impermeable to the passage of fluid. An exit portin the wall connects a drug in the compartment with the exterior of thedelivery device. The device comprises a first and second compositioncomprising a mixture of methylcellulose, agar and carboxymethylcelluloseor a mixture of hydroxypropylmethylcellulose and sodiumcarboxymethylcellulose. The patents do not teach regulating andcontrolling the thixotropic behavior of the composition for deliveringsubstantially all of the drug and concomitantly the release ratebehavior characteristics of the delivery device.

The prior art in U.S. Pat. No. 4,816,263 issued to Ayer, Swanson andKuczynski; in U.S. Pat. No. 4,837,111 issued to Deters, Wong, Barclay,Theeuwes and Swanson; in U.S. Pat. No. 4,859,470 issued to Guittard,Wong, Theeuwes and Cortese; in U.S. Pat. No. 4,863,456 issued toStephens and Wong; in U.S. Pat. No. 4,902,514 issued to Barclay, Wong,Wright and Childers; in U.S. Pat. No. 4,946,687 issued to Ayer, Swansonand Kuczynski; in U.S. Pat. No. 4,948,593 issued to Wright, Childers,Barclay, Wong and Atkinson; in U.S. Pat. No. 4,950,486 issued to Ayer,Swanson and Kuczynski; and in U.S. Pat. No. 4,966,769 issued toGuittard, Wong, Theeuwes and Cortese, the patentees disclosed deliverydevices comprising a composition comprising a drug and a compositioncomprising a polymer for pushing the drug from the device, however,these patents do not teach two different molecular weight polymersoperating together to avoid residual drugs in the device at the end ofthe drug delivery period. The prior art devices of the above patents areeffective for their intended purpose, but they do not teach a uniquedifference and an accompanying cooperating relationship between twocompositions comprising dissimilar polymers for controlled drug deliveryover time.

It will be appreciated by those versed in the drug delivery art, that ifa delivery device is provided that comprises different internalcompositions that exhibit a high level of hydrodynamic and osmoticactivity for delivery a drug at a controlled rate for therapy, such adelivery device would have a positive value and represent an advancementin the delivery art. Likewise, it will be immediately appreciated bythose versed in the dispensing art that if a delivery device is madeavailable possessing thermodynamic activity for delivering controlleddoses of a drug, such a dispensing device would find a practicalapplication in pharmacy and in medicine. Now, it has been found thatdelivery devices can be enhanced by using different hydrogel polymersfor providing maximum self-delivery of drug and maximum self-expansionof the polymer for urging substantially all of the drug from the device.

OBJECTS OF THE INVENTION

Accordingly, in view of above presentation, it is an immediate object ofthis invention to provide a dosage form manufactured as a drug deliverydevice for providing an advancement over the prior art.

Another object of the invention is to provide a dosage form manufacturedas a delivery device comprising a first composition and a differentsecond composition for delivering essentially all of a drug to a patientover time.

Another object of the invention is to provide a dosage form comprising afirst composition comprising a drug and a selected cellulose polymer anda second composition comprising a different selected cellulosic polymerfrom the polymer in the first composition for improving the deliverycharacteristics of the dosage form.

Another object of the invention is to provide a dosage form comprisingtwo separate compositions with each composition comprising a differentmolecular weight polymer for delivering a drug at a controlled rate overa prolonged period of time from 30 minutes to 24 hours.

Another object of the invention is to provide a dosage form fordelivering in vivo a calcium channel blocking drug that can be deliveredfrom the device by using two different polymers for good therapy.

Another object of the invention is to provide a dosage form thatembraces an osmotic structure possessing two compositions that operateas an integrated unit, which dosage form comprises a first osmoticcomposition comprising a drug and an osmopolymer, and a secondcomposition comprising a different osmopolymer, which first and secondcompositions act in concert for hydrodynamically and osmoticallydelivering the drug from the osmotic dosage form.

Another object of the invention is to provide an osmotic dosage formhaving means for high loading of from 10 nanograms to 750 milligrams ofa water soluble or a water insoluble calcium channel blocking drug fordelivering the drug by the interaction to two compositions comprisingdifferent polymers for delivering the drug at a controlled rate andcontinuously over time to a drug recipient.

Another object of the invention is to provide an osmotic dosage formcomprising a first composition comprising an osmopolymer and a secondcomposition comprising a different osmopolymer which osmopolymersgenerate distinct osmotic activities independent of the otherosmopolymer, but both cooperating to deliver the drug from the device.

Another object of the invention is to provide an osmotic dosage formthat can administer a complete pharmaceutical dosage regimen fordelivering a calcium channel blocking drug at a controlled rate andcontinuously for a given time period, the use of which requiresintervention only for initiation and possible termination of thetherapeutic regimen.

Another object of this invention is to provide an osmotic dosage formwhich can house a calcium channel blocking drug and dispense the drug insmall doses per hour average at a controlled rate to thegastrointestinal tract throughout the length of the gastrointestinaltract following oral administration of the dosage form.

Another object of the invention is to provide an osmotic dosage formmanufactured with a compartment comprising a first polymer compositionand a second different polymer composition in contacting arrangementthat simultaneously maintain their original identity and function as anintegrated compositional layers for delivering a drug from the dosageform.

Another object of the invention is to provide a dosage form comprisingosmopolymers manufactured free-of-irradiation such as gamma rays,thereby eliminating any potentially dangerous source or irradiation fromthe dosage form and from a patient.

Another object of the invention is to provide a dosage form free ofpoly(alkylene oxide) for administering a drug to a recipient in need ofcontrolled drug therapy.

Another object of the invention is to provide an osmotic dosage formcomprising osmopolymers made free-of-radiation for enhancing theacceptance of the dosage form by a patient and by a physician.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawing figures, which are not drawn to scale, but are set forthto illustrate various embodiments of the invention, the drawing figuresare as follows:

Drawing FIG. 1 is a view of an osmotic dosage form sized, shaped andadapted for oral administration into the gastrointestinal tract of apatient in need of drug therapy;

Drawing FIG. 2 is an opened view of the osmotic dosage form of drawingFIG. 1 with part of the wall of the dosage form removed for illustratingthe structure of the dosage form;

Drawing FIG. 3 is a graph that depicts the cumulative amount of drugdelivered by the dosage form over time.

In the drawings and in the specification like parts in related figuresare identified by like parts. The terms appearing earlier in thespecification and in the description of the drawings, as well asembodiments thereof, are further detailed elsewhere in the disclosure.

DETAILED DESCRIPTION OF THE DRAWING FIGURES

Turning now to the drawing figures in detail, which drawing figures arean example of the dosage form provided by the invention and whichexample is not to be considered as limiting, one example of an osmoticdosage form is illustrate in drawing FIG. 1 and in drawing FIG. 2.

In drawing FIG. 1, an osmotic dosage form is seen designated by thenumeral 10. Dosage form 10 comprises a body member 11 comprising a wall12 that surrounds and defines an internal compartment, not visible indrawing FIG. 1. Dosage form 10 comprises at least one passageway 13 thatconnects the interior of dosage form 10 with the exterior biologicalenvironment of use.

In drawing FIG. 2, osmotic dosage form 10 is seen in opened view at 14for illustrating the internal structure of dosage form 10. In drawingFIG. 2, dosage form 10 comprises a body 11 and wall 12. Wall 12surrounds, forms and defines an internal compartment 15. Wall 12comprises one passageway 13, or optionally, more than one exitpassageway, for dispensing a drug 16 (represented by dots) fromcompartment 15 of dosage form 10. Drug 16 is defined herein, comprisesany drug that can be delivered from dosage form 10 to produce atherapeutic useful result in a patient. In the present application, theterm "drug" includes any physiologically or pharmacologically activesubstance that produces a local or a systemic effect in animals,including warm-blooded mammals, including humans. The drugs that can bedelivered by dosage form 10 comprise drugs that are insoluble to highlysoluble in aqueous fluids including biological fluids. In one presentlypreferred embodiment drug 16 comprises a calcium channel blocking drug.

Wall 12 of dosage form 10 comprises a composition that is permeable tothe passage of an exterior fluid present in a biological environment ofuse, and it is substantially impermeable to the passage of drug 16, itssalts or its derivatives, and to other ingredients in compartment 15.Wall 12 is substantially inert, nontoxic and it maintains its physicaland chemical integrity during the drug dispensing life of dosage form10. The phrase, "maintains its physical and chemical integrity" meanswall 12 does not lose its physical structure during the dispensing lifeof dosage form 10. Wall 12, in one presently preferred embodiment,comprises a member selected from the group consisting of a celluloseester, a cellulose ether, or a cellulose ester-ether. In a morepresently preferred embodiment, wall 12 comprises a member selected fromthe group consisting of a cellulose acylate, cellulose diacylate,cellulose triacylate, cellulose acetate, cellulose diacetate, andcellulose triacetate. The cellulose polymeric members comprising wall 12comprise cellulose acetate having a degree of substitution up to 1 andan acetyl content up to 21%, a cellulose diacetate having a degree ofsubstitution of 1 to 2 and an acetyl content of 21% to 35%, a cellulosetriacetate having a degree of substitution of 2 to 3 and an acetylcontent of 35% to 44%. The amount of a cellulosic polymer present inwall 12 of dosage form 10 is from 85 weight percent (wt %) to 100 wt %.The cellulosic polymers are known to the art in U.S. Pat. Nos.3,845,770; 3,816,899; 4,859,470; and 4,863,456; and in Handbook ofCommon Polymers, by J. R. Scott and W. J. Roff, (1971) published by CRCPress Inc., Cleveland, Ohio. Wall 12 comprises optionally, a fluxenhancer, such as a polyethylene glycol that aids in governing fluidflux through semipermeable wall 12. The flux enhancer polyethyleneglycol comprises a molecular weight range of 1500 to 7500. Theconcentration of polyethylene glycol in wall 12, optionally, comprisesfrom 1 wt % to 15 wt %, with the total concentration of the ingredientscomprising wall 12 equal to 100 wt %.

Compartment 15, in a drug composition, also identified as a firstcomposition, comprises 20 wt % to 98 wt % of an alkalicarboxymethylcellulose ether 17, identified by a wavy line, blended withdrug 16. The present invention unexpectedly discovered acarboxymethylcellulose ether 17, or its nontoxic alkali salt, can beused as a thixotropic transport means for drug 16. The amount of drug 16present in compartment 15 is 2 wt % to 45 wt %. Thecarboxymethylcellulose ether 17, includes sodium or potassiumcarboxymethylcellulose, and it possesses an initial gel flow-resistantstrength. The carboxymethylcellulose 17 comprising drug 16 on contact byaqueous fluid imbibed into dosage form 10 transforms into a dispensable,thixotropic transport aqueous drug formulation. This dispensable drugformulation, in the presence of a separate osmotic-push force generatedin dosage form 10, is subjected to a shear stress applied to theformulation resulting in the formulation being pushed through exit port13 over 24 hours. The alkali carboxymethylcellulose 17, operable fortransporting drug 16 comprises a degree of polymerization of 20 to1,200, a 10,000 to 300,000 molecular weight and a viscosity of 25 to1750 cps, centipoises, in a 2% aqueous solution at 25° C. The drugformulation in a preferred manufacture comprises 0 to 40%polyvinylpyrrolidone 18, represented by a vertical line, and comprisinga 15,000 to 75,000 molecular weight, from 0 to 40 wt %hydroxypropylcellulose 19, represented by a slant line, comprising a20,000 to 80,000 molecular weight, and from 0 to 5 wt % of a lubricantsuch as magnesium stearate, calcium stearate, or stearic acid, with theweight of all ingredients comprising the drug formulation, or the firstcomposition, equal to 100 wt %.

Dosage form 10, in compartment 15, comprises a push formulation 20. Pushformulation 20, also identified as a second composition, when dosageform 10 is in operation imbibes a fluid, expands and then pushes thedrug composition through exit 13 from dosage form 10. Push composition20 comprises 6.5 wt % to 100 wt % of a carboxymethylcellulose 21comprising a greater than 300,000 to 1,200,000 molecular weight and adegree of polymerization of greater than 1,200 to 4,500. Pushcomposition in a preferred manufacture comprises from 0 wt % to 25 wt %of an osmagent 22, represented by circles, selected from the groupconsisting of an osmotically active salt, an osmotically activecarbohydrate, osmotically active polysaccharide, an osmotically activeoxide, or an osmotically active acid solute, from 0 wt % to 25 wt %hydroxypropylmethylcellulose 23, represented by a square, comprising a9,200 to 20,000 molecular weight, from 0 to 5 wt % lubricant comprisingmagnesium stearate, stearic acid, or calcium stearate, and 0 to 3 wt %ferric oxide, with the weight of all ingredients in push formulationequal to 100 wt %.

The expression, "exit passageway 13," comprises means and methodssuitable for dispensing the beneficial drug 16 from dosage form 10. Theexit means includes one passageway, or more than one passageway, thatpasses through wall 12 for communicating drug 16 in compartment 15 withthe exterior of dosage form 10. The expression, "one passageway,"includes aperture, orifice, bore, pore, porous element through whichdrug 16 can be dispensed, a hollow fiber, capillary tube, microporousinsert, or microporous overlay. Thus, a wall that is in part microporousis optional with the invention. The expression includes a material thaterodes or is leached from wall 12 int he fluid environment of use toproduce one passageway, or more than one passageway, of controlled exitreleasing dimensions. Representative materials suitable for forming atleast one passageway, two passageways, or more, include an erodiblepoly(glycolic) or poly(lactic) acid member in the wall, a gelatinousfilament, poly(vinyl alcohol), leachable materials such as fluidremovable pore formers providing exit pores of release rate controllingproperties. A passageway or a plurality of passageways can be formed byleaching a material such as sorbitol, mannitol or sodium chloride fromthe wall. The passageway can have any shape such as round, triangular,square, elliptical, or irregular. The dosage form can be constructedwith one or more passageways in a spaced apart relation or a singlesurface or on more than more distant surfaces of a dosage form.Passageways and equipment for forming passageways are disclosed in U.S.Pat. Nos. 3,916,899; 4,063,064 and 4,088,864. Representative passagewaysformed by governed leaching of a fluid leachable composition to producea pore of controlled release rate size are disclosed in U.S. Pat. No.4,200,098.

Dosage form 10 is manufactured by standard techniques. For example, inone manufacture a drug and the other ingredients comprising the drugformulation are homogeneously blended and pressed into a solidformulation. The pressed formulation possesses dimensions thatcorrespond to the internal dimension of the area occupied by the drugformulation in the dosage form 10. The drug formulation also possessesdimensions corresponding to the dimensions of the push formulation forforming a contacting surface arrangement therewith. In this manufacture,the drug and the other ingredients comprising the compositions areblended with a solvent and mixed into a solid or semisolid form byconventional methods such as ballmilling, calendering, stirring orrollmilling and then pressed into a preselected shape. Next, the pushcomposition is placed in contact with the drug composition. The drugcomposition, push composition can be placed in contacting arrangement byusing a conventional two-layered press. The contacting drug compositionand push composition are coated with a semipermeable wall. The wall canbe applied by compression coating, molding, spraying, dipping, or airsuspension procedures. The air suspension and the air tumblingprocedures comprise suspending and tumbling the pressed drug compositionand the push composition in a current of air containing the wall formingcomposition. The dosage forms provided by the invention can embrace manyshapes for administering a drug. The dosage form, for example, can beround-shaped, square-shaped, oval-shaped, bean-shaped, or caplet-shaped.The dosage form can be manufactured for sublingual administration,buccal administration or gastrointestinal administration.

In another manufacture, dosage form 10 is manufactured by the wetgranulation technique. In the wet granulation technique, the drug andthe ingredients comprising the drug composition are blended using anorganic cosolvent, such as isopropyl alcohol-methylene dichloride 80/20v/v (volume/volume) as the granulation fluid. The ingredients formingthe drug composition are passed through a 40 mesh screen and thoroughlyblended in a mixer. Other optional ingredients comprising the drugcomposition are dissolved in a portion of the granulation fluid andadded to the drug blend with continual mixing in the blender. Thegranulating fluid is added until a blend is produced, which wet blend isthen forced through a 20 mesh screen onto oven trays. The blend is driedfor 18 to 24 hours at 50° C. in a forced air oven. The dried granulesare then sized through a 20 mesh screen. Next, a lubricant such asmagnesium stearate, which has been passed through an 80 mesh screen, isadded to the drug screened granules and blended in a V-blender for 5 to10 minutes. The composition is pressed into a layer, for example, in a3-station Manesty® layer press. The speed of the press is set at 30 rpmand the maximum load set at 2 tons. The drug layer is pressed againstthe push composition and the bi-layer, drug-push core fed to a coatingmachine.

Another manufacturing process that can be used for providing the drugcomposition, push composition comprises blending the powderedingredients comprising the drug composition, or the push compositionseparately in a fluid bed granulator. After the powdered ingredients aredry blended in the granulator, a granulating fluid, for example,poly(vinylpyrrolidone) in water, is sprayed onto the powders. The coatedpowders then are dried in the granulator. This process granulates allthe ingredients present therein while adding the granulating fluid.After the granules are dried, a lubricant, such as stearic acid ormagnesium stearate, is added to the granules in a V-blender and blended5 to 10 minutes. The granules then are pressed in the manner describedabove.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLE 1

An osmotic dosage form for the controlled and continuous release of thedrug nifedipine, and antianginal drug belonging to the pharmacologicaldrugs called the calcium channel blockers, that inhibits thetransmembrane influx of calcium ions into cardiac muscles and smoothmuscles is made as follows: first, 200 g of nifedipine, 300 g ofhydroxypropylcellulose, possessing a 60,000 molecular weight, 295 g ofsodium carboxymethylcellulose, possessing a 90,000 molecular weight and100 g of polyvinylpyrrolidone possessing a 40,000 molecular weight areblended into a mass and then screened through a 40-mesh screen. Then,the screened composition is placed into a Glatt fluid bed granulator,blended and slightly warmed to 35° C. to yield a homogeneous mass. Next,a granulating solution consisting of 100 g of polyvinylpyrrolidonepossessing a 40,000 molecular weight in 400 ml of purified water issprayed onto the fluidized powders.

After initiation of the spraying cycle, the process is monitored toinsure formation of acceptable uniformity. The granules are dried insitu and delumped by screening through a 16-mesh screen. Next, 5 g ofmagnesium stearate is screened through an 80 mesh screen, added to thegranules in the blender, and blended to a uniform composition. Thecomposition produced by this process comprised 20 wt % nifedipine, 30 wt% hydroxypropylcellulose, 29.5 wt % of sodium carboxymethylcellulose, 20wt % of polyvinylpyrrolidone and 0.5 wt % of magnesium stearate. Thecomposition is divided into a drug formulation for making dosage formswherein the drug formulation comprises 60 mg of nifedipine, 90 mg ofhydroxypropylcellulose, 88.5 mg of sodium carboxymethylcellulose, 60 mgof polyvinylpyrrolidone and 1.5 mg of magnesium stearate.

Next, a push formulation is made in an identical manner. First, 788 g ofsodium carboxymethylcellulose comprising a 700,000 molecular weight, 10g of ferric oxide, and 50 g of polyvinylpyrrolidone comprising a 40,000molecular weight, are screened through a 40-mesh screen, followed byscreening 100 g of sodium chloride through a 60 mesh screen. The twoscreened materials are blended and warmed to 30° C. in a fluid bedgranulator. Next, a granulating solution comprising 50 g ofpolyvinylpyrrolidone comprising a 40,000 molecular weight in 400 ml ofdistilled water, is sprayed onto the granules. Next, the granules areblended and added to a fluid bed granulator. A granulating solution of50 g polyvinylpyrrolidone of 40,000 molecular weight in distilled wateris coated onto the granules as prepared in the fluidized bed. Then, thegranules are dried in situ and delumped by screening through a 16-meshscreen. Then, two grams of magnesium stearate are screened through an 80mesh screen, and added to the granules in a blender and blended atmoderate blending speed for 7 minutes. The composition formed by thisprocess comprises 78.8 wt % sodium carboxymethylcellulose comprising a700,000 molecular weight, 10 wt % of sodium chloride, 10 wt % ofpolyvinylpyrrolidone comprising a 40,000 molecular weight, 1.0 wt %ferric oxide, and 0.2 wt % of magnesium stearate. The same composition,divided into a push composition for forming the second composition in adosage form comprises, expressed in mg as follows: 118.2 mg sodiumcarboxymethylcellulose comprising a 700,000 molecular weight, 15 mg ofsodium chloride, 15 mg of polyvinylpyrrolidone having a 40,000 molecularweight, 1.5 mg of ferric oxide, and 0.3 mg of magnesium stearate.

The drug composition and the push composition, next are fed to a bilayertablet press and pressed into a bilayer core. Then, a wall formingcomposition comprising 90 wt % cellulose acetate comprising a 39.8%acetyl content, and 10 wt % polyethylene glycol comprising a 3350molecular weight, are dissolved in a 90 wt % methylene chloride and 10wt % methanol cosolvent and is coated around the bilayer cores in asuspension coater. Then, a 25 mil, 0.650 mm, orifice is laser drilled inthe center of the wall facing the drug side. Next, the delivery devicesare dried in a humidity oven to remove any residual solvent. The devicesare overcoated with an inert coat to enhance their appearance.

The delivery system provided by the present invention uses acarboxymethylcellulose in the drug formulation; and a different andhigher molecular weight carboxymethylcellulose in the push formulation.The use of two different molecular weight carboxymethylcellulosepolymers provides an unexpected result over the prior art. That is, inthe prior art U.S. Pat. No. 4,783,337, a composition prepared accordingto the patent, comprising a drug and a 200,000 molecular weight polymer,resulted in a residual drug concentration in the dosage form in excessof 11.1%; also a dosage form provided by the prior art comprising a drugand a 300,000 molecular weight polymer leaves a residual concentrationof 14.7% drug in the dosage form. The present invention unexpectedlyfound that a dosage form comprising two different molecular weightcarboxymethylcellulose with the higher molecular weightcarboxymethylcellulose in the push formulation exhibited as little as3.7% residual drug in the dosage form at the end of the drug deliveryperiod. This invention's improvement in drug delivery is unforseen andit enhances significantly the use of the present dosage form forimproved drug therapy. With the present dosage form, both the physicianand the patient know the patient is receiving substantially the intendedprescribed dose of drug for drug therapy. The accompanying drawing FIG.3 denotes the total concentration of a drug, exemplified by nifedipine,delivered over time.

EXAMPLE 2

A formulation for administering a drug to a patient according to claim1, wherein the formulation comprises a dose amount of an orallyadministrable drug, a hydroxypropylcellulose, a polyvinylpyrrolidone anda carboxymethylcellulose of 10,000 to 300,000 molecular weight.

EXAMPLE 3

A formulation for administering a drug to a patient according to claim1, wherein the formulating comprises a dose amount of nifedipine,hydroxypropylcellulose, polyvinylpyrrolidone and carboxymethylcellulose,comprising a 10,000 to 300,000 molecular weight.

EXAMPLE 4

A dosage form for orally administering a drug to a patient is providedaccording to claim 1, wherein the drug nifedipine is replaced by amember selected from the group consisting of verapamil, diltiazem,bepridil, nicardipine, nitredipine, isradipine, niludepine, nisoldipine,felodipine, cinnarizine, flunarizine, perhexiline, and amlodipine, andwherein the patient is in need of a calcium channel blocking therapy.

EXAMPLE 5

A dosage form for delivering diltiazem is made as follows: first 9.40 kgof diltiazem hydrochloride, 0.20 kg of sodium carboxymethylcellulosecomprising a 200,000 molecular weight, 0.10 kg of hydroxypropylcellulosecomprising a 30,000 molecular weight are added to a blender and blendedfor 15 minutes to produce a uniform blend. Next, 0.20 kg ofpolyvinylpyrrolidone having a 38,000 molecular weight is mixed with 350ml of anhydrous ethyl alcohol to form a granulation fluid. Then, thegranulation fluid is added slowly to the blended ingredients, and allthe ingredients blended to produce a wet mass. The wet mass is dried ina forced air oven for 17 to 23 hours at room temperature, about 25° C.,to evaporate the ethyl alcohol. Then, the dry granules are given anadditional drying for 2 to 4 hours at 50° C. The dry granules are thenpassed through a 30 mesh screen. Next, 0.10 kg of the lubricantmagnesium stearate is added to the drug blend and blended for 9 minutesto produce a homogeneous composition.

Next, a push composition is made as follows: first, 4.35 kg of sodiumcarboxymethylcellulose having a 650,000 molecular weight, 0.35 kg ofsodium chloride and 0.25 kg of hydroxypropylmethylcellulose having a11,200 molecular weight are blended for 10 minutes to yield a uniformblend. Next, 350 ml of denatured anhydrous ethyl alcohol is added as agranulating fluid to yield a wet mass. Next, the granulated wet mass ispassed through a 30 mesh screen to form wet granules. The wet granulesnext are spread onto trays, and the wet granules dried at roomtemperature of 25° C. for 20 to 25 hours. The dry granules then arepassed through a 20 mesh screen. The push composition now is ready formanufacturing into the final device.

The granules comprising the diltiazem are transferred to the number onefeed inlet of a hopper and the granules comprising the push compositionare fed to the number two feed inlet of a hopper. The feed hoppers areplaced onto a bi-layer press and the diltiazem composition pressed ontothe push composition.

Next, the pressed compositions are surrounded with a semipermeable wall.The wall forming composition is prepared as follows: first, a cosolventis prepared by mixing 80 parts of methylene chloride with 20 parts ofmethanol (wt/wt) and cellulose acetate having an acetyl content of 39.8%is slowly added thereto. Then, polyethylene glycol having a 3350molecular weight is added to the freshly prepared ingredients. Then, thepressed dual compositions are placed in a coating unit, and the presseddual compositions coated with a semipermeable wall.

Next, the wall coated compositions are removed from the coater and anexit port of 24 mil, 0.609 mm, is drilled through the wall by a laser.The dosage forms are dried in a humidity oven at 50% relative humidityat 50° C. for 48 hours to remove wall traces of residual solvent. Thedosage forms are sized and shaped for oral admittance into thegastrointestinal tract of a human. The controlled release dosage formsprovided by this manufacture comprises a dose of 360 mg of diltiazemthat is delivered for a prolonged period of up to 24 hours.

EXAMPLE 6

The above procedures are followed in this example to provide (a)sustained-release, oral osmotic caplets comprising 40 mg, 80 mg, 120 mg,240 mg or 480 mg of verapamil pharmaceutically acceptable salt; (b)sustained-release, oral osmotic caplets comprising 30 mg, 60 mg, 90 mg,120 mg, 240 mg or 480 mg of diltiazem pharmaceutically acceptable salt;or (c) extended-release, oral osmotic caplets comprising 20 mg, 30 mg,45 mg, 60 mg, 90 mg or 120 mg of nifedipine for the relaxation andprevention of coronary artery spasm, for reduction of oxygen requirementand for the reduction of arterial blood pressure.

EXAMPLE 7

The above procedures are followed in this example to provide a dosageform wherein the drug composition comprises the drug nitredipine,polyvinylpyrrolidone, sodium carboxymethylcellulose, comprising a 70,000molecular weight, sodium lauryl sulphate and hydroxypropylcellulose.

EXAMPLE 8

The above procedure is followed in this example, with the added Hembodiment comprising blending from 0.1 wt % to 15 wt % of vitamin B₂,also known as riboflavin, with the drug nifedipine for impartingprotection against the adverse effects of light on nifedipine, and alsoblending a surface active agent with the nifedipine to enhance thefluidic dispensing properties of the drug formulation from the dosageform. The surface active agent, operable for the intended purpose,consists of a member selected from the group consisting of anionic,cationic, and nonionic surface active agents, exemplified by Pluronics,Cremophors, polyoxyalkylene fatty acid esters, polyoxyalkylene fattyacid ethers, and alkoxylated hydrogenated castor oils. The surfaceactive agent is present in a concentration of from 0.01 wt % to 15 wt %with the concentration of all ingredients in the formulation equal to100 wt %.

METHOD OF PRACTICING THE INVENTION

This example pertains to a method for delivering a drug to a humanpatient in need of therapy, which method comprises:

(A) admitting orally into the human a dosage form comprising:

(1) a wall comprising at least in part a semipermeable composition, saidwall surrounding, defining and forming a compartment, which compartmentcomprises:

(a) a drug composition comprising from 10 ng to 750 mg of drug, 20 to 98wt % of a carboxymethylcellulose comprising a 10,000 to 300,000molecular weight, 0 to 40 wt % of a hydroxypropylcellulose comprising a15,000 to 75,000 molecular weight, 0 to 40 wt % of apolyvinylpyrrolidone comprising a 20,000 to 40,000 molecular weight, and0 to 5 wt % of a lubricant;

(b) a push composition comprising from 65 wt % to 100 wt % of acarboxymethylcellulose comprising a molecular weight greater than300,000 to 1,200,000, and from 0 to 25 wt % of an osmagent, and from 0to 25 wt % of a polyvinylpyrrolidone comprising a 20,000 to 40,000molecular weight;

(2) a passageway in the wall for delivering the drug from the device;and,

(B) delivering the drug from the dosage form by imbibing fluid from thepatient into the compartment to form a dispensable drug composition andto form an expanding push composition for pushing the drug through thepassageway to the human in need of drug therapy.

In summary, it will be appreciated the present invention contributes tothe drug delivery art an unobvious dosage form that possesses practicalmedical utility. While the invention has been described and pointed outin detail with reference to operative embodiments thereof, it will beunderstood that those skilled in the art will appreciate that variouschanges, modifications, substitutions and omissions can be made withoutdeparting from the spirit of the invention. It is intended, therefore,that the invention embraces those equivalents within the scope of theclaims.

We claim:
 1. A method for administering a drug to the gastrointestinaltract of a patient, which method comprises,(a) admitting a dosage formorally into a patient, said dosage form comprising:(1) a first layercomprising 10 ng to 750 mg of drug; (2) a second layer for pushing thefirst layer from the dosage form; (3) a wall surrounding the first andsecond layers, the wall comprising at least in part, a compositionpermeable to the passage of fluid; (4) an exit passageway in the wallfor delivering the drug from the dosage form to the patient; and whereinsaid, (5) first layer comprises an alkali carboxymethylcellulosecomprising a 10,000 to 300,000 molecular weight; and said, (6) secondlayer comprises an alkali carboxymethylcellulose comprising a molecularweight greater than 300,000; and wherein the dosage form when in use ischaracterized by said: (7) first layer possessing an initialflow-resistant that is changed in the presence of imbibed fluid into adispensable aqueous drug layer; and said: (8) second layer pushing thefirst layer through the exit passageway, with each alkalicarboxymethylcellulose maintaining its original separate identities andfunctions; thereby, (b) administering the drug by the first and secondlayers cooperating to administer substantially all the drug to thepatient over time.
 2. The method for administering a drug to thegastrointestinal tract of a patient wherein the method comprises:(a)admitting a dosage form orally into the patient, said dosage formcomprising:(1) a first composition comprising 10 ng to 750 mg of a drugselected from the group consisting of nifedipine, verapamil, diltiazem,bepridil, nicardipine, nitredipine, isradipine, and niludepine; (2) asecond composition for pushing the first composition from the dosageform; (3) a wall surrounding the first and second compositions, the wallcomprising at least in part, a composition permeable to the passage offluid; (4) an exit passageway in the wall for delivering the drug fromthe dosage form to the patient; and wherein said, (5) first compositioncomprises a member selected from the group consisting of a potassium andsodium carboxymethylcellulose comprising a 10,000 to 300,000 molecularweight; and said, (6) second composition comprises a member selectedfrom the group consisting of a potassium and sodiumcarboxymethylcellulose comprising a molecular weight greater than300,000; and, (b) administering the drug by the first and secondcomposition cooperating to administer substantially all the drug to thepatient over time.
 3. The method for administering the drug to thegastrointestinal tract of the patient according to claim 2, wherein thedrug is replaced by a different drug selected from the group consistingof nisoldipine, felodipine, cinnarizine, flunarizine, perhexiline andamlodipine.
 4. The method for administering the drug to thegastrointestinal tract according to claim 1, wherein the drug is acalcium channel blocking drug.
 5. The method for administering the drugto the gastrointestinal tract according to claim 1, wherein the firstcomposition comprises sodium lauryl sulphate.
 6. The method foradministering the drug to the gastrointestinal tract of the patientaccording to claim 1, wherein the passageway is formed by eroding anagent in the wall to provide a release rate controlling pore passageway.7. The method for administering the drug to the gastrointestinal tractof the patient according to claim 1, wherein the passageway is formed bylaser drilling the passageway in the wall.